Regulatory Decision Summary for Sandoz Bisoprolol Tablets
Review decision
The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.
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What was the purpose of this submission?
The purpose of this New Drug Submission (NDS) for Sandoz Bisoprolol (a submission relying on Third Party Data) was to add two new lower strength oral tablets, 1.25 mg and 2.5 mg, for the management of patients with mild to moderate hypertension. The two strengths previously approved, 5 and 10 mg, are also for the treatment of mild to moderate hypertension. The submission was also seeking approval for a new active ingredient supplier, a new formulation and appearance (cross score notch for the 5 mg and 10 mg), a new manufacturing site and packaging sites for drug product, as well as a change in manufacturing process and batch size.
Why was the decision issued?
A Notice of Deficiency (NOD) was issued for several reasons. Firstly, the sponsor failed to provide a systematic review of the literature, so it was not possible to determine if a comprehensive, unbiased review of the scientific literature was completed or if the evidence provided included all relevant studies related to the efficacy and safety of low dose bisoprolol for the treatment of mild to moderate hypertension.
Secondly, the evidence provided to support the two proposed lower doses was insufficient. Of the 125 references provided, only three evaluated the efficacy of the 2.5 mg dose for the treatment of mild to moderate hypertension; none assessed the 1.25 mg dose. Actual changes in blood pressure (the outcome directly linked to the proposed indication) were reported in only two of the three relevant studies. While some of the studies were described as double blinded and randomized, sufficient details were lacking to verify if this was the case. In addition, the studies were very small (from 11 to 59 patients). Because of limited reporting, there was insufficient evidence to reach a favorable regulatory decision.
Lastly, the evidence from the three studies reporting on changes in blood pressure associated with low dose bisoprolol (2.5 mg/day) were contradictory. In one study, all patients on this low dose were up-titrated to 5 or 10 mg/day because the low dose was not sufficient to manage their hypertension. In another study, 2.5 mg/day was considered effective at managing hypertension and in the third, blood pressure decreased, but the decrease was considerably less than the standard reductions reported with most anti-hypertensives used in monotherapy.
In response to a Notice of Deficiency, the two new strengths were withdrawn and the submission focussed on the manufacturing changes for the existing approved products.
In the Product Monograph (PM) filed with the Response to the NOD, all reference to the proposed lower doses (1.25 and 2.5 mg) were removed.
There were also some minor concerns related to drug quality that were included in the NOD. In the response to the NOD and follow-up communications, all of the outstanding quality issues were resolved.
There were no concerns with the Comparative Bioavailability Findings, as the study provided met the applicable bioequivalence standards for bisoprolol.
In their response, the sponsor has adequately addressed all of Health Canadas concerns. A Notice of Compliance was issued.
Decision issued
Approved; issued a Notice of Compliance in accordance with the Food and Drug Regulations.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| SANDOZ BISOPROLOL TABLETS | 02494043 | SANDOZ CANADA INCORPORATED | BISOPROLOL FUMARATE 10 MG |
| SANDOZ BISOPROLOL TABLETS | 02494035 | SANDOZ CANADA INCORPORATED | BISOPROLOL FUMARATE 5 MG |